Work in our laboratory spanning more than two decades has demonstrated that certain drugs may be attached to well-defined carrier molecules and still retain the ability to bind to the receptor site and effect biological activity. This synthetic strategy for the attachment of drugs to carriers is termed the functionalized congener approach. The carrier molecule may be many times larger than the parent drug; indeed there is practically no maximum size limitation for a fully potent analog. Unlike the prodrug approach or the immobilization of drugs for slow release, the functionalized congener approach is designed to produce analogs for which no metabolic cleavage step is necessary for activation. Moreover, the attachment of the drug to a carrier such as a peptide may result in enhanced affinity at an extracellular receptor site and an improvement in the pharmacological profile of the parent drug through energetically favorable interaction with distal sites on a receptor. [unreadable] [unreadable] Purine derivatives containing attached chains to target distal sites of GPCRs have been developed as functionalized congeners that either activate or antagonize adenosine receptors, and a similar strategy has been used for ATP receptors. For example, the 2-position of the purine moiety has been identified for attachment of functionalized chains in ATP derivatives as P2X and P2Y receptor agonists. Reporter groups such as fluorescent dyes have been covalently attached resulting in receptor probes of relatively high affinity. The targeting of distal sites on the calcium sensing receptor has also been studied.[unreadable] [unreadable] Other means of altering pharmacokinetics of a known drug include the prodrug approach. We have prepared prodrugs of adenosine A3 agonists and antagonists, e.g. nuceloside derivatives, that are not themselves biologically active, but are able to be regenerated in biological systems. Studies of the cleavage of the blocked ligands indicates that the prodrugs are suitable as masked forms of the biologically active A3AR agonists and antagonists for future evaluation in vivo.[unreadable] [unreadable] The use of GPCR agonists for therapy has inherent limitations. The distribution of a given receptor in multiple tissues may lead to undesired side effects. Also, the desensitization of a receptor upon repeated agonist exposure may limit agonist utility. We are developing an alternate approach to achieve the beneficial effects of GPCR activation in a more spatially and temporally selective manner than the systemic administration of agonists to the native GPCR. This approach of neoceptors combines small molecule classical medicinal chemistry and gene or cell therapy. By this rational design approach, complementary structural changes are made in the receptor and ligand for selective enhancement of affinity. The spatially-selective activation of a neoceptor would be dependent on cell- or organ-target delivery of the gene. Molecular modeling, of GPCRs has been used widely to arrive at hypotheses for recognition of antagonists and agonists by ligand docking. We have are validated hypotheses for docking of ligands at purine receptors using site-directed mutagenesis. Site-directed mutagenesis and molecular modeling have been used to characterize the ligand binding sites of the P2Y1 and A3 receptors to predict which regions of a given ligand may be amenable to a chain attachment approach. With this knowledge and the ability to tailor-make new analogues of a native agonist, one may design a matched neoceptor and neoligand, i.e. the binding site of a given GPCR may be engineered to recognize synthetic agonist ligands that do not activate the native receptor. Distal sites of interaction on the engineered receptor may be targeted to allow selective enhancement of affinity in a functionalized congener. Based on predictions from molecular modeling, we have designed neoceptors for A2A and A3 adenosine receptors, in which a tailored ligand activates only engineered receptor. The success of the neoceptor strategy for the ARs validates the use of homology modeling, as well as suggests options for future therapeutics.